The oral cavity is a "portal of entry" for bacteria, fungi and other infectious agents that reach the respiratory and gastrointestinal tracts. Lining these tracts is the MALT, which can induce immunity or oral tolerance against bacteria species. The antigen-presenting cells known as DCs form a discrete microanatomical organization with T cells in MALT Peyer's patch, which is crucial for initiation and regulation of the immune response. Work from our laboratory and others have established the human oral mucosa as a rich repository of DCs. We presently understand little about the function and organization of DCs in these tissues. This R21 application proposes the hypothesis that, if proven, will support a new paradigm - that adaptive immunity is regulated at several levels by: (1) distinct DCs subsets that infiltrate the oral mucosa; (2) TLRs expressed; and (3) the antigens encountered. Our overall hypothesis is that the human oral mucosal DCs play pivotal roles in regulation of the adaptive immune response to specific antigens. The sub-hypotheses are: (1) distinct DC subsets infiltrate different microanatomical sites in the gingival/buccal mucosa; (2) these DC subsets are differentially responsive to LPS and other antigens by virtue of the expression of antigen-selective TLR2 and TLR4; and (3) the T cell response to antigens is regulated by DC responsiveness. The present application proposes the following aims: Aim 1: To characterize the DC subsets that infiltrate human oral mucosa in health and disease; and Aim 2: To determine the ability of DC subsets to regulate the T cell response to antigens in vitro. The PI has assembled a team of investigators with expertise in microbiology, oral pathology/stomatology, immuunohistochemistry, LPS purification/characterization, DC/Langerhans cell function and T cell function to carry out these studies. The investigators are all located on the Dallas campus of the Baylor Medical Center Hospital, including Baylor College of Dentistry-TAMUS and the Baylor Institute for Immunology Research. It is hoped this research will advance our understanding of how adaptive immunity to microbial antigens is initiated and regulated at the mucosal level. Our short-term objective is to acquire sufficient preliminary data/publications to facilitate the successful submission of an R01 proposal(s). Our long-term objective is to develop this research to the level of a program project on DCs and the mucosal immune response.